The canonical Wnt/p-catenin pathway is constitutively activated in multiple myeloma cells and is necessary for their growth and survival. Our work has further demonstrated that the MUC1 oncoprotein is aberrantly expressed in multiple myeloma cells and that the MUC1-C receptor subunit binds directly to pcatenin. The interaction between MUC1-C and p-catenin stabilizes p-catenin and contributes to the nduction of Wnt target genes. The available evidence indicates that MUC1-C functions as a novel chaperone that interacts with effectors, such as p-catenin, that regulate growth and survival. In this regard, other studies have shown that MUC1-C activates the kBa kinase complex and thereby the NF-icB pathway. MUC1-C is also targeted to mitochondria by HSP90 where it attenuates activation of the intrinsic apoptotic response. These findings have supported a model in which MUC1-C functions in integrating Wnt/p-catenin ignaling with other pathways that have been linked to the growth and survival of multiple myeloma cells. Our hypothesis is that targeting the Wnt/p-catenin pathway is a rational approach for the treatment of multiple myeloma. The proposed studies thus focus on the role of MUC1-C in activating Wnt/p-catenin signaling in multiple myeloma cells and on the development of agents that disrupt this pathway. Our work will also define the involvement of MUC1-C in integrating Wnt/p-catenin signaling with activation of the IKKp- >NF-icB pathway and HSP90-dependent targeting of MUC1-C to mitochondria for the development of rationally based combinations. Agents that target the Wnt/p-catenin pathway will thus be studied alone and in combination for effects on myeloma cell growth and survival in the bone marrow microenvironment and in xenograft models. The results of these studies will be used to design clinical trials of Wnt/p-catenin inhibitors alone and in combination for the treatment of patients with refractory multiple myeloma. The Specific Aims are: 1) To define the role of the MUC1-C receptor in activation of the Wnt/p-catenin pathway in multiple myeloma cells; 2) To determine the function of MUC1-C in integrating Wnt/p-catenin signaling with the NF-KB and HSP90 pathways; 3) To study the effects of blocking Wnt/p-catenin signaling, alone and in combination, on multiple myeloma cell growth and survival in the bone marrow milieu in vitro and in xenograft models of human multiple myeloma; and 4) To perform Phase l/ll clinical trials of therapies targeting Wnt/p-catenin alone and in combination for the treatment of multiple myeloma. Relevance: The translations! studies and clinical trials proposed in this Project focus on the development of inhibitors of the Wnt/p-catenin pathway as a novel approach alone and in combination for the treatment of multiple myeloma.